Late-Breaking Study Published in NEJM Finds Rivaroxaban Superior to Aspirin for Long-Term Prevention of Recurrent Blood Clots in Patients with VTE

New Phase 3 Study Finds XARELTO® to Be Superior to Aspirin for Long-Term Prevention of Recurrent Blood Clots Without Observing any Significant Increase in Major Bleeding in Patients with Venous Thromboembolism
 
·       EINSTEIN CHOICE was presented as a late-breaker at the American College of Cardiology's 66th Annual Scientific Session and published simultaneously in The New England Journal of Medicine  

·       Phase 2 GEMINI-ACS-1 study also presented as a late-breaker and published simultaneously in The Lancet, showing similar safety between XARELTO® (rivaroxaban) and aspirin in patients with acute coronary syndrome also taking a P2Y12 inhibitor
 

WASHINGTON, DC (March 18, 2017) – Janssen Pharmaceuticals, Inc. (Janssen) today announced new Phase 3 results from EINSTEIN CHOICE showing patients with venous thromboembolism (VTE) taking XARELTO® (rivaroxaban), who received either 10 mg or 20 mg once daily over an extended time period, had significantly fewer recurrent blood clots and similar rates of major bleeding compared to those taking aspirin 100 mg once daily. Specifically, XARELTO® 10 mg reduced the risk of recurrent VTE by 74 percent and XARELTO® 20 mg by 66 percent.
These findings were presented today during a Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials session at the American College of Cardiology's 66th Annual Scientific Session (ACC.17) and published simultaneously in The New England Journal of Medicine. EINSTEIN CHOICE is part of the industry-leading EXPLORER clinical research program for XARELTO®, a collaborative effort between Janssen and its development partner, Bayer.
VTE, which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), affects more than 900,000 Americans each year; one-third of these occurrences are fatal.[i] As all people with VTE are at risk of having another occurrence, guidelines currently recommend anticoagulant therapy with a non-vitamin K antagonist oral anticoagulant (NOAC), like XARELTO®, for three months or longer.[ii]

Once anticoagulant therapy is stopped, up to 10 percent of people will experience a recurrence during the first year and up to 20 percent within three years.[iii] In people who decide to stop anticoagulant therapy, guidelines currently suggest using aspirin for long-term prevention of recurrent VTE rather than no aspirin at all.ii The EINSTEIN CHOICE study was designed to compare the efficacy and safety of XARELTO® to aspirin for continued VTE management.

"How best to extend anticoagulant use beyond the initial treatment window has been a constant source of debate, with physicians carefully balancing patients’ risk of another VTE with the risk of anticoagulant-related bleeding," said study investigator Philip S. Wells, MD, Professor, Chair and Chief, Department of Medicine, University of Ottawa, and Senior Scientist, The Ottawa Hospital, Ontario, Canada. "With EINSTEIN CHOICE, for the first time we have clinical evidence confirming rivaroxaban is superior to aspirin in reducing recurrent VTE, with no significant impact on safety. These important results have the potential to trigger a paradigm shift in how physicians manage their patients and protect them from VTE recurrence over the long term."

EINSTEIN CHOICE met its primary endpoint, finding both XARELTO® doses (10 mg and 20 mg) to be superior to aspirin in preventing recurrent VTE. Researchers observed the following:
·       The rate of recurrent VTE was 1.2 percent in the XARELTO® 10 mg group (HR=0.26; 95% CI, 0.14 to 0.47; p<0.001) and 1.5 percent in the XARELTO® 20 mg group (HR=0.34; 95% CI, 0.20 to 0.59; p<0.001) compared to 4.4 percent in the aspirin group. Fatal VTE occurred in 0 percent, 0.2 percent and 0.2 percent, respectively.
·       Rates of major bleeding were comparable and low across all treatment groups at 0.4 percent for XARELTO® 10 mg (HR=1.64; 95% CI, 0.39 to 6.84; p=0.50), 0.5 percent for XARELTO® 20 mg (HR=2.01; 95% CI, 0.50 to 8.04; p=0.32) and 0.3 percent for aspirin. Rates of clinically relevant non-major bleeding also were similar between the groups at 2.0 percent, 2.7 percent and 1.8 percent, respectively.
Other efficacy outcomes were evaluated in the study. Researchers found 1.9 percent of the XARELTO® 10 mg group (HR=0.33; 95% CI, 0.20 to 0.54; p<0.001) and 2.0 percent of the XARELTO® 20 mg group (HR=0.35; 95% CI, 0.22 to 0.57; p<0.001) experienced either a recurrent VTE (primary efficacy endpoint), heart attack, ischemic stroke, systemic embolism or venous thrombosis in another location compared to 5.6 percent of the aspirin group. Recurrent VTE or all-cause mortality occurred in 1.3 percent of the XARELTO® 10 mg group (HR=0.27; 95% CI, 0.15 to 0.47; p<0.001) and 2.1 percent of the XARELTO® 20 mg group (HR=0.42; 95% CI, 0.26 to 0.68; p<0.001) compared to 4.9 percent of the aspirin group. When looking at pre-specified subgroups, researchers found results for the primary efficacy endpoint (recurrent VTE) and composite outcome of major and clinically relevant non-major bleeding to be consistent with the overall findings.
"In addition to confirming findings from previous studies examining the long-term use of XARELTO® in VTE, EINSTEIN CHOICE provides valuable clinical insights on the superiority of XARELTO® to aspirin as well as the potential extended use of a lower dose of XARELTO® for continued venous protection,” said Paul Burton, MD, PhD, FACC, Vice President, Medical Affairs, Janssen. "We look forward to discussing these important data with the U.S. Food and Drug Administration."
EINSTEIN CHOICE was led by principal investigator Jeffrey Weitz, MD, Professor of Medicine, Michael G. DeGroote School of Medicine, McMaster University, and Director of McMaster’s Thrombosis & Atherosclerosis Research Institute. This Phase 3, global, randomized, double-blind, superiority study compared the efficacy and safety of two doses of XARELTO® (a prophylactic dose of 10 mg once daily and a treatment dose of 20 mg once daily) with aspirin 100 mg once daily for the continued management of VTE in people with confirmed DVT or PE who were initially treated with anticoagulant therapy for six to 12 months. Approximately 3,365 patients from 31 countries were included in the study analysis. Importantly, people who required extended anticoagulation at therapeutic doses were not included, as the objective of the study was to investigate those patients for whom the treating physician was uncertain about the need for continuing anticoagulant therapy.
Patients were randomized in a 1:1:1 ratio, with one group receiving XARELTO® 10 mg, another group receiving XARELTO® 20 mg, and a third receiving aspirin 100 mg, all given once daily for up to 12 months. Sixty percent of patients completed the full 12 months of treatment. The primary efficacy endpoint was fatal or non-fatal recurrent VTE (a composite of recurrent VTE, VTE-related death and unexplained death for which PE could not be excluded). The primary safety endpoint was major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH). Only the primary efficacy outcome comparisons of XARELTO® 10 mg vs. aspirin and XARELTO® 20 mg vs. aspirin were powered for significance. Comparison of the two XARELTO® arms was not powered for significance.
 
Late-Breaking Phase 2 GEMINI-ACS-1 Results
Also presented today during the same Joint American College of Cardiology/Journal of the American Medical Association Late-Breaking Clinical Trials session at ACC.17 and published simultaneously in The Lancet were results from the Phase 2 GEMINI-ACS-1 study, which investigated the safety of XARELTO® 2.5 mg twice daily compared to aspirin 100 mg once daily when added to a P2Y12 inhibitor (clopidogrel or ticagrelor) for the secondary prevention of cardiovascular events in patients with acute coronary syndrome (ACS). This early stage, double-blind, randomized study of 3,037 patients met its primary endpoint, showing similar safety with XARELTO® compared to aspirin in this ACS population.
Specifically, GEMINI-ACS-1 researchers observed Thrombolysis in Myocardial Infarction (TIMI) clinically significant bleeding in 5.3 percent of the XARELTO® group and 4.9 percent of the aspirin group (HR=1.09; 95% CI, 0.80 to 1.50; p=0.58), with similar rates of severe/major bleeding (according to TIMI bleeding definitions) also noted between the groups.
Researchers also examined several exploratory efficacy endpoints. For the composite efficacy endpoint (which included cardiovascular death, heart attack, stroke or stent thrombosis), the two groups had similar rates, with 5.0 percent of the XARELTO® group and 4.7 percent of the aspirin group (HR=1.06; 95% CI, 0.77-1.46; p=0.73) experiencing a cardiovascular event. For all-cause death and the individual components of the composite efficacy endpoint, rates also were similar between the two groups.
"With slightly more than one million Americans discharged from the hospital each year with either a primary or secondary diagnosis of ACS,[iv] it is important for the scientific community to continue investigating different treatment approaches for vascular protection aimed at preventing secondary cardiovascular events in these patients," said Dr. Burton. "Results from this preliminary study find XARELTO® and aspirin to have similar safety post-ACS, and we intend to use this research to inform future plans for examining XARELTO® in this population."

About EXPLORER
Both EINSTEIN CHOICE and GEMINI-ACS-1 are part of the EXPLORER clinical research program for XARELTO®. The EXPLORER program is unmatched by any oral anticoagulant in the NOAC class in its size, scope and ambition. A collaborative effort between Janssen and Bayer, EXPLORER seeks to generate important clinical evidence on the safety and efficacy of XARELTO® and its potential role in addressing critical unmet medical needs. A number of the studies are designed to seek additional indications or expand the label for XARELTO®. By the time of its completion, more than 275,000 patients will have participated in the EXPLORER clinical development program, other completed and ongoing clinical trials, investigative registries and non-interventional studies.